Bystander Signalling: Exploring Clinical Relevance Through New Approaches and New Models

Classical radiation biology research has centred on nuclear DNA as the main target of radiation-induced damage. Over the past two decades, this has been challenged by a significant amount of scientific evidence clearly showing radiation-induced cell signalling effects to have important roles in mediating overall radiobiological response. These effects, generally termed radiation-induced bystander effects (RIBEs) have challenged the traditional DNA targeted theory in radiation biology and highlighted an important role for cells not directly traversed by radiation. The multiplicity of experimental systems and exposure conditions in which RIBEs have been observed has hindered precise definitions of these effects. However, RIBEs have recently been classified for different relevant human radiation exposure scenarios in an attempt to clarify their role in vivo. Despite significant research efforts in this area, there is little direct evidence for their role in clinically relevant exposure scenarios. In this review, we explore the clinical relevance of RIBEs from classical experimental approaches through to novel models that have been used to further determine their potential implications in the clinic. 

Effect of membrane stiffness and cytoskeletal element density on mechanical stimuli within cells: an analysis of the consequences of ageing in cells

A finite element model of a single cell was created and used to investigate the effects of ageing on biophysical stimuli generated within a cell. Major cellular components were incorporated in the model: the membrane, cytoplasm, nucleus, microtubules, actin filaments, intermediate filaments, nuclear lamina, and chromatin. The model used multiple sets of tensegrity structures. Viscoelastic properties were assigned to the continuum components. To corroborate the model, a simulation of Atomic Force Microscopy (AFM) indentation was performed and results showed a force/indentation simulation with the range of experimental results.

Ageing was simulated by both increasing membrane stiffness (thereby modelling membrane peroxidation with age) and decreasing density of cytoskeletal elements (thereby modelling reduced actin density with age). Comparing normal and aged cells under indentation predicts that aged cells have a lower membrane area subjected to high strain compared to young cells, but the difference, surprisingly, is very small and would not be measurable experimentally. Ageing is predicted to have more significant effect on strain deep in the nucleus. These results show that computation of biophysical stimuli within cells are achievable with single-cell computational models whose force/displacement behaviour is within experimentally observed ranges. the models suggest only small, though possibly physiologically-significant, differences in internal biophysical stimuli between normal and aged cells.

Agency or Dependency?: The Mixed Peppers Theatre Arts Training Project for young people with disabilities

This article provides a reflection on my past practice as Creative Director of The Mixed Peppers Theatre Arts Training Programme. Drawing upon discourses of Disability Studies it considers how this ostensibly emancipatory project that sought to provide access to theatre activity for young people with physical disabilities living in Northern Ireland was flawed, and was eventually disbanded, partly due to a failure on the part of its non-disabled leadership to address imbalances of power in its relationship with its young disabled constituency. The article is framed within a survey of recent debates that focus upon the historical lack of a sustained, indigenous, disability-led theatre activity in Northern Ireland and the recent efforts by non-disabled professional arts practitioners to establish such activity in the region. It offers, as an exemplar to current discussion, an analysis of how the choice and agency of the young members of The Mixed Peppers were compromised by the well-meaning but potentially oppressive practices of its leadership. It questions whether the project was unduly influenced by parental desire to see their disabled children `normalized' in a high-profile theatrical production. Finally, it considers how The Mixed Peppers' institutional situation, as a project controlled and administered by a disability charity, was implicated in the premature demise of the initiative.

Formal calibration methodology for CFD models of naturally ventilated indoor environments

Well planned natural ventilation strategies and systems in the built environments may provide healthy and comfortable indoor conditions, while contributing to a significant reduction in the energy consumed by buildings. Computational Fluid Dynamics (CFD) is particularly suited for modelling indoor conditions in naturally ventilated spaces, which are difficult to predict using other types of building simulation tools. Hence, accurate and reliable CFD models of naturally ventilated indoor spaces are necessary to support the effective design and operation of indoor environments in buildings. This paper presents a formal calibration methodology for the development of CFD models of naturally ventilated indoor environments. The methodology explains how to qualitatively and quantitatively verify and validate CFD models, including parametric analysis utilising the response surface technique to support a robust calibration process. The proposed methodology is demonstrated on a naturally ventilated study zone in the library building at the National University of Ireland in Galway. The calibration process is supported by the on-site measurements performed in a normally operating building. The measurement of outdoor weather data provided boundary conditions for the CFD model, while a network of wireless sensors supplied air speeds and air temperatures inside the room for the model calibration. The concepts and techniques developed here will enhance the process of achieving reliable CFD models that represent indoor spaces and provide new and valuable information for estimating the effect of the boundary conditions on the CFD model results in indoor environments. © 2012 Elsevier Ltd.

MIXED-MODEL PRODUCTION SYSTEM DESIGN FOR AIRCRAFT ASSEMBLY

With the advancement of flexible fixture and flexible tooling, mixed production has become possible for aircraft assembly as the manufacturing processes of different aircraft/sub-assembly models are similar. However, it is a great challenge to model the problem and provide a practical solution due to the low volume and complex constraints of aircraft assemblies. To tackle this problem, this work proposes a methodology for designing the mixed production system, and a new scheduling approach is proposed by combined backward and forward scheduling methods. These methods are validated through a real-life industrial case study. Simulation results show that the number of workstations and the cycle time for making a fuselage can be reduced by 50% and 39% respectively with the newly designed mixed-model system.

Biomechanics of Vertebroplasty: Effect of Cement Viscosity on Mechanical Behaviour

Vertebroplasty is a minimally invasive surgical procedure, which requires efficacious percutaneous cement delivery via a cannulated needle to restore the strength and stiffness in osteoporotic vertebral bodies. Cement viscosity is understood to influence the injectability, cohesion and cement retention within the vertebral body. Altering the liquid to powder ratio modifies the viscosity of bone cement; however, the cement viscosity-response association between cement fill and augmentation of strength and stiffness is unknown. The aim of this study was to determine the relationship between viscosity, cement fill and the potential augmentation of strength and stiffness in an open pore foam structure that was representative of osteoporotic cancellous bone using an in vitro prophylactic vertebroplasty model. The results showed a strong linear correlation between compressive strength and stiffness augmentation with percentage cement fill, the extent of which was strongly dependent on the cement viscosity. Significant forces were required to ensure maximum delivery of the high viscosity cement using a proprietary screw-driven cement delivery technology. These forces could potentially exceed the normal human physical limit. Similar trends were observed when comparing the results from this study and previously reported cadaveric and animal based in vitro models.

Behavioural context of multi-scale species distribution models assessed by radio-tracking

Incorporating ecological processes and animal behaviour into Species Distribution Models (SDMs) is difficult. In species with a central resting or breeding place, there can be conflict between the environmental requirements of the 'central place' and foraging habitat. We apply a multi-scale SDM to examine habitat trade-offs between the central place, roost sites, and foraging habitat in . Myotis nattereri. We validate these derived associations using habitat selection from behavioural observations of radio-tracked bats. A Generalised Linear Model (GLM) of roost occurrence using land cover variables with mixed spatial scales indicated roost occurrence was positively associated with woodland on a fine scale and pasture on a broad scale. Habitat selection of radio-tracked bats mirrored the SDM with bats selecting for woodland in the immediate vicinity of individual roosts but avoiding this habitat in foraging areas, whilst pasture was significantly positively selected for in foraging areas. Using habitat selection derived from radio-tracking enables a multi-scale SDM to be interpreted in a behavioural context. We suggest that the multi-scale SDM of . M. nattereri describes a trade-off between the central place and foraging habitat. Multi-scale methods provide a greater understanding of the ecological processes which determine where species occur and allow integration of behavioural processes into SDMs. The findings have implications when assessing the resource use of a species at a single point in time. Doing so could lead to misinterpretation of habitat requirements as these can change within a short time period depending on specific behaviour, particularly if detectability changes depending on behaviour. © 2011 Gesellschaft für ökologie.

A systematic review and meta-analysis of the ethnic density effect in psychotic disorders

A number of studies have found an ethnic density effect in psychotic disorders, where the incidence for ethnic minorities increases as the neighbourhood proportional ethnic composition decreases [Morgan and Hutchinson, Psychol Med 40:705-709, (2010); Singh, Psychol Med 39:1402-1403, (2009); Schofield et al., Psychol Med 41:1263-1269, (2010)]. However, there is a mixed picture with some studies reporting no effect [Schofield et al., Psychol Med 41:1263-1269, (2010)]. This review aimed to establish the existence of the effect by answering the review question: is there an ethnic density dose effect in the prevalence of psychotic disorders?

Nonlinear numerical modelling of lightning strike effect on composite panels with temperature dependent material properties

This paper presents a physics based modelling procedure to predict the thermal damage of composite material when struck by lightning. The procedure uses the Finite Element Method with non-linear material models to represent the extreme thermal material behaviour of the composite material (carbon/epoxy) and an embedded copper mesh protection system. Simulation predictions are compared against published experimental data, illustrating the potential accuracy and computational cost of virtual lightning strike tests and the requirement for temperature dependent material modelling. The modelling procedure is then used to examine and explain a number of practical solutions to minimize thermal material damage. © 2013 Elsevier Ltd.

Synergistic effects of proteasome inhibitor carfilzomib in combination with tyrosine kinase inhibitors in imatinib-sensitive and -resistant chronic myeloid leukemia models

The tyrosine kinase inhibitor (TKI) imatinib has transformed the treatment and outlook of chronic myeloid leukemia (CML); however, the development of drug resistance and the persistence of TKI-resistant stem cells remain obstacles to eradicating the disease. Inhibition of proteasome activity with bortezomib has been shown to effectively induce apoptosis in TKI-resistant cells. In this study, we show that exposure to the next generation proteasome inhibitor carfilzomib is associated with a decrease in ERK signaling and increased expression of Abelson interactor proteins 1 and 2 (ABI-1/2). We also investigate the effect of carfilzomib in models of imatinib-sensitive and -resistant CML and demonstrate a potent reduction in proliferation and induction of apoptosis in a variety of models of imatinib-resistant CML, including primitive CML stem cells. Carfilzomib acts synergistically with the TKIs imatinib and nilotinib, even in imatinib-resistant cell lines. In addition, we found that the presence of immunoproteasome subunits is associated with an increased sensitivity to carfilzomib. The present findings provide a rational basis to examine the potential of carfilzomib in combination with TKIs as a potential therapy for CML, particularly in imatinib-resistant disease.

Effect of the crown design and interface lute parameters on the stress-state of a machined crown-tooth system: A finite element analysis

The effect of preparation design and the physical properties of the interface lute on the restored machined ceramic crown-tooth complex are poorly understood. The aim of this work was to determine, by means of three-dimensional finite element analysis (3D FEA) the effect of the tooth preparation design and the elastic modulus of the cement on the stress state of the cemented machined ceramic crown-tooth complex. The three-dimensional structure of human premolar teeth, restored with adhesively cemented machined ceramic crowns, was digitized with a micro-CT scanner. An accurate, high resolution, digital replica model of a restored tooth was created. Two preparation designs, with different occlusal morphologies, were modeled with cements of 3 different elastic moduli. Interactive medical image processing software (mimics and professional CAD modeling software) was used to create sophisticated digital models that included the supporting structures; periodontal ligament and alveolar bone. The generated models were imported into an FEA software program (hypermesh version 10.0, Altair Engineering Inc.) with all degrees of freedom constrained at the outer surface of the supporting cortical bone of the crown-tooth complex. Five different elastic moduli values were given to the adhesive cement interface 1.8 GPa, 4 GPa, 8 GPa, 18.3 GPa and 40 GPa; the four lower values are representative of currently used cementing lutes and 40 GPa is set as an extreme high value. The stress distribution under simulated applied loads was determined. The preparation design demonstrated an effect on the stress state of the restored tooth system. The cement elastic modulus affected the stress state in the cement and dentin structures but not in the crown, the pulp, the periodontal ligament or the cancellous and cortical bone. The results of this study suggest that both the choice of the preparation design and the cement elastic modulus can affect the stress state within the restored crown-tooth complex.

Pharmacological evaluation of selective α2c-adrenergic agonists in experimental animal models of nasal congestion

Nasal congestion is one of the most troublesome symptoms of many upper airways diseases. We characterized the effect of selective α2c-adrenergic agonists in animal models of nasal congestion. In porcine mucosa tissue, compound A and compound B contracted nasal veins with only modest effects on arteries. In in vivo experiments, we examined the nasal decongestant dose-response characteristics, pharmacokinetic/pharmacodynamic relationship, duration of action, potential development of tolerance, and topical efficacy of α2c-adrenergic agonists. Acoustic rhinometry was used to determine nasal cavity dimensions following intranasal compound 48/80 (1%, 75 µl). In feline experiments, compound 48/80 decreased nasal cavity volume and minimum cross-sectional areas by 77% and 40%, respectively. Oral administration of compound A (0.1-3.0 mg/kg), compound B (0.3-5.0 mg/kg), and d-pseudoephedrine (0.3 and 1.0 mg/kg) produced dose-dependent decongestion. Unlike d-pseudoephedrine, compounds A and B did not alter systolic blood pressure. The plasma exposure of compound A to produce a robust decongestion (EC(80)) was 500 nM, which related well to the duration of action of approximately 4.0 hours. No tolerance to the decongestant effect of compound A (1.0 mg/kg p.o.) was observed. To study the topical efficacies of compounds A and B, the drugs were given topically 30 minutes after compound 48/80 (a therapeutic paradigm) where both agents reversed nasal congestion. Finally, nasal-decongestive activity was confirmed in the dog. We demonstrate that α2c-adrenergic agonists behave as nasal decongestants without cardiovascular actions in animal models of upper airway congestion.

On the nudging terms at open boundaries in regional ocean models

For open boundary conditions (OBCs) in regional models, a nudging term added to radiative and/or advective conditions during the wave or flow propagation outward from the model domain of interest is widely used, to prevent the predicted boundary values from evolving to become quite different from the external data, especially for a long-term integration. However, nudging time scales are basically unknown, leading to many empirical selections. In this paper, a method for objectively estimating nudging time scales during outward propagation is proposed, by using internal model dynamics near the boundary. We tested this method and other several commonly used OBCs for cases of both an idealized model domain and a realistic configuration, and model results demonstrated that the proposed method improves the model solutions. Many similarities are found between the nudging and mixing time scales, in magnitude, spatial and temporal variations, since the nudging mainly replaces the effect of the mixing terms in this study. However, the mixing time scale is not an intrinsic property of the nudging term because in other studies the nudging term might replace terms other than the mixing terms and, thus, should reflect other characteristic time scales.

Filling the gap: A 60 ky record of mixed carbonate-siliciclastic turbidite deposition from the Great Barrier Reef

Late Pleistocene to Holocene margin sedimentation on the Great Barrier Reef, a mixed carbonatesiliciclastic margin, has been explained by a transgressive shedding model. This model has challenged widely accepted sequence stratigraphic models in terms of the timing and type of sediment (i.e. carbonate vs. siliciclastic) deposited during sea-level oscillations. However, this model documents only hemipelagic sedimentation and the contribution of coarse-grained turbidite deposition, and the role of submarine canyons in this process, remain elusive on this archetypal margin. Here we present a new model of turbidite deposition for the last 60 ky in the north-eastern Australia margin. Using highresolution bathymetry, 58 new and existing radiometric ages, and the composition of 81 turbidites from 15 piston cores, we found that the spatial and temporal variation of turbidites is controlled by the relationship between sea-level change and the variable physiography along the margin. Siliciclastic and mixed carbonate-siliciclastic turbidites were linked to canyons indenting the shelf-break and the welldeveloped shelf-edge reef barriers that stored sediment behind them. Turbidite deposition was sustained while the sea-level position allowed the connection and sediment bypassing through the interreef passages and canyons. Carbonate turbidites dominated in regions with more open conditions at the outer-shelf and where slope-confined canyons dominated or where canyons are generally less abundant. The turn-on and maintenance of carbonate production during sea-level fluctuations also influenced the timing of carbonate turbidite deposition. We show that a fundamental understanding of the variable physiography inherent to mixed carbonate-siliciclastic margins is essential to accurately interpret deep-water, coarse-grained deposition within a sequence stratigraphic context. 

Power-Capped DVFS and Thread Allocation with ANN Models on Modern NUMA Systems

Abstract—Power capping is an essential function for efficient power budgeting and cost management on modern server systems. Contemporary server processors operate under power caps by using dynamic voltage and frequency scaling (DVFS). However, these processors are often deployed in non-uniform memory
access (NUMA) architectures, where thread allocation between cores may significantly affect performance and power consumption. This paper proposes a method which maximizes performance under power caps on NUMA systems by dynamically optimizing two knobs: DVFS and thread allocation. The method selects the optimal combination of the two knobs with models based on artificial neural network (ANN) that captures the nonlinear effect of thread allocation on performance. We implement
the proposed method as a runtime system and evaluate it with twelve multithreaded benchmarks on a real AMD Opteron based NUMA system. The evaluation results show that our method outperforms a naive technique optimizing only DVFS by up to
67.1%, under a power cap.